Influenza virus evolution precludes long lasting natural or vaccine induced immunity to IAV, and is the cause of yearly vaccine reformulation. Antigenic variation in the hemagglutinin (HA) glycoprotein is the sine qua non of human influenza A viruses (IAVs). Despite its importance, we have only a limited understanding of the molecular mechanisms underlying influenza virus evolution in vivo. To study virus changes in the context of natural in vivo transmission, we aim to set up a guinea pig transmission model of influenza virus infection. We have recently shown that many of the HA mutations that occur during viral passage in mice result in alterations in HA receptor affinity. We are following these changes in a natural model of influenza transmission and also examining modifications that may occur in the viral NA because the NA and HA must work together to enable viral entry and release from cells.